CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987) and it is suggested that CRF plays central roles in bioreactions in stress (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). CRF acts in two pathways: one acting on the peripheral immune system and sympathetic nervous system via the hypothalamus-pituitary-adrenal system, and another in which it acts as: a neurotransmitter in the central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp 29-52, 1990). In the case where CRF is intraventricularly administered to hypophysectomized rats and to normal rats, symptoms of anxiety occur in both rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). Therefore, it is believed that CRF is involved in the hypothalamus-pituitary-adrenal system and that CRF functions as a neurotransmitter in the central nervous system.
The diseases in which CRF is involved are summarized in a review by Owens and Nemeroff in 1991 (Pharmacol. Rev., 43, 425-474, 1991). Namely, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, digestive tract diseases, drug dependence, inflammation, immune system-related diseases, and the like. Recently, it is reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and head trauma (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997), and for this reason, CRF-receptor antagonists are useful as therapeutic agents for these diseases.
An objective of the present invention is to provide CRF antagonists effective on therapeutic agents or prophylactic agents for the diseases, which CRF participates in, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, digestive apparatus disease, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune system-related diseases.